Radiosynthesis of carbon‐11‐labelled GI181771, a new selective CCK‐A agonist

Abstract

SummaryThe novel CCK-A agonist, (S)-3-(3-f1-[(isopropylphenylcarbamoyl)methyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo [b][1,4]diazepin-3-ylgureido)benzoic acid, GI181771 ((S)-1) has been isotopically labelled with carbon-11 at its urea site using [ 11 C]phosgene in a one-pot two-step process, via the intermediate preparation of an specific radioactivities ranging from 500 to 1500 mCi/mmol (18.5-55.5 GBq/mmol). The radiotracer preparation was a clear and colourless solution and its pH was between 5 and 7. As demonstrated by HPLC analysis, the radiolabelled product was found to be >99% chemically and radiochemically pure and the preparation was shown to be free of non-radioactive precursors (starting amines) and radiochemically stable for at least 60 min. Finally, enantiomeric purity was found to be >99%

Palladium‐mediated oxidative carbonylation reactions for the synthesis of 11C‐radiolabelled ureas

“…Following heating, the contents of the vial were transferred to a quench vial containing water (0.3 mL). Argon was bubbled through the resultant mixture in order to transfer any unreacted 11 CO into the waste bag. The vial was then removed from the hot cell; its radioactivity was measured, and a 20-μL aliquot was removed for HPLC analysis.…”

“…Urea functional groups are an obvious target for [ 11 C]CO radiolabelling as this group is found in many biologically relevant molecules. Traditionally, [ 11 C]ureas have been prepared using [ 11 C]phosgene, a reagent that is notoriously difficult to prepare in a reliable manner and is used at only a few PET facilities worldwide. Alternatively, [ 11 C]ureas have been synthesized from [ 11 C]CO at high pressures using selenium or rhodium catalysts; however, these approaches are restricted to the formation of cyclic or symmetrical species (with selenium) or require the synthesis of an azide precursor (with rhodium).…”

“…[ 11 C]Carbon monoxide ([ 11 C]CO) can be synthesized readily in one step from cyclotron-generated [ 11 C]CO 2 and has the potential to be a versatile 11 C-labelling reagent; yet, its widespread use has been restricted by its low solubility and its delivery at low concentrations. Over the past 15 years, a number of groups have made considerable progress in this field, with [ 11 C]CO emerging as a viable labelling reagent through the use of high-pressure reactors, 4,5 [ 11 C]CO trapping solutions, 6,7 and most recently, additive-free techniques that allow for excellent [ 11 C]CO trapping either through the use of xenon gas delivery 8 or the presence of a highly reactive palladium-xantphos trapping/catalytic species. 9 This work has demonstrated the potential value of this radiolabelling reagent, with a range of [ 11 C]carbonyl-containing compounds having been synthesized, typically through transition metalcatalysed reactions.…”

Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

“…The effects observed during fasting suggested that the CCK1R mechanisms may be pharmacologically targeted to alter fasting gastric function. With the aim of using this agonist as a radioligand for molecular and functional imaging studies by positron emission tomography (PET), 32a has been labeled with the positron emitter isotope 11 C at the ureido group carbon [63]. Additionally, to further explore the binding sites of 1,5-benzodiazepine-derived agonists and antagonists at the CCK1 receptor, the two resolved enantiomeric pairs of benzophenone derivatives 32b,c and 32d,e, previously reported as racemic agonists and antagonists, respectively [64], have been recently prepared labeled with 14 C also at the ureido group, to be used as radioligands and photoaffinity probes [65].…”

State of Art in 11C Labelled Radiotracers Synthesis

“…[ 11 C]Benazoline was obtained in 16% overall yield, relative to [ 11 C]CO 2 and with a specific radioactivity of 54 GBq/mmol., decay corrected from end of irradiation. In order to get a better understanding of this system, investigations for the radiolabelling feasibility of GI181771, CCK-A agonist, with carbon-11 were realized [271]. In order to get a better understanding of this system, investigations for the radiolabelling feasibility of GI181771, CCK-A agonist, with carbon-11 were realized [271].…”